Objective. To examine the role of ASAH1/acid ceramidase in GBA1-associated Parkinson’s disease (PD). Hypothesis. Acid ceramidase plays a key role in the accumulation of pathogenic ⍺-synuclein species. Background. GlcSph is a neurotoxic sphingolipid generated through an alternative activation of the lysosomal enzyme acid ceramidase. We previously showed that mutant GBA1 interferes with the autophagy/lysosomal pathway (ALP) in neuronopathic Gaucher disease (nGD) neurons, and that acid ceramidase inhibition rescued the ALP by lowering levels of GluSph. We asked whether this pathogenic pathway was also active in GBA1-associated PD. Methods. Our experimental system was iPSC-derived DA neurons from PD patients harboring heterozygous mutations in GBA1 (N370S/WT, L444P/WT, and RecNciI/WT), and the corresponding gene-edited WT/WT controls. We then determined the effect of acid ceramidase inhibitors, and genetic knockdown of ASAH1 on ⍺-synuclein accumulation and aggregation in DA neurons. Findings. Mutant GBA1-DA neurons exhibited a-synuclein aggregation, and acid ceramidase inhibition by 4 different inhibitors, as well as genetic ASAH1 knockdown, were sufficient to reverse the ⍺-synuclein phenotype to isogenic control levels. The deleterious effects of acid ceramidase were due to dysregulation of an mTOR/TFEB/Cath D/ALP cascade, which interfered with ⍺-synuclein clearance. Conclusion. We postulate that persistent generation of GlcSph by acid ceramidase in GBA1/PD-DA neurons is a key pathogenic event leading to suppression of normal lysosomal functions, interfering with the clearance of α-synuclein. The results validate acid ceramidase as a therapeutic target, strongly suggesting that its inhibition may be an effective substrate reduction therapy, to prevent or ameliorate neurodegeneration in nGD and GBA1-associated PD.